A new way to ‘prime the tumor environment’ could boost the effectiveness of chemotherapy for pancreatic cancer ductal carcinoma, which is one of the most deadly forms pancreatic cancer.
Preclinical studies show that a Garvan Institute of Medical Research team could increase tumors’ response against chemotherapy by reducing the stiffness and density of connective tissue, also known as the stroma. This could reduce cancer spread by upto 50%.
The research has led to a clinical trial that will test whether the treatment method is effective for patients suffering from pancreatic ductal cancer.
“By making cancer cells more sensitive to chemotherapy, we hope to improve survival rates for pancreatic cancer patients,” says Professor Paul Timpson, Cancer Research Theme Director at the Garvan Institute and co-senior author of the research findings published in Science Advances. “This research is an impressive example of advanced research in the laboratory which has led to partnerships with industry and a potential clinical translation.”
New treatment for one of the most deadly cancers
Pancreatic ductal carcinomama, a deadly type of pancreatic cancer is the most frequent. Despite the advancements in chemotherapy strategies that combine both the 5-year survival rate is less than one in ten and below 3 percent if cancer has already metastasized.
We wanted to try and enhance chemotherapy by using a unique approach – targeting the surrounding environment around the tumor to make the cancer more tolerant to treatment.”
Dr. Kendelle Murphy, who was the first author of the paper.
FAK, the pancreatic cancer molecule that improves stiffness and assists cancer cells in their growth, mobilization and metastasis, was studied by the researchers. Using state-of-the-art intravital imaging techniques to reveal how live pancreatic cancers in mouse models respond to treatment, the researchers looked into whether blocking FAK using an experimental therapy could trigger cancer cells to be more easily destroyed by chemotherapy.
Dr. Murphy states that the best results were obtained when the treatment targeted FAK prior to chemotherapy in our experimental models.
“By treating tumors in advance with FAK inhibitors we were able to alter both the stiffness and amount and deposition of the stromal tissues that surround cancer cells. The cancer cells became more tolerant to chemotherapy because of this softened surface. We were enhancing the vulnerability of these cancer cells to chemotherapy, which in turn slowed pancreatic cancer growth and spread in various models.
A method to determine who will be the most benefit
The researchers also discovered that levels of another protein in pancreatic cancer cells, known as Merlin, could help in determining those who could benefit the most from FAK targeting.
“Merlin, a protein that is produced in different amounts in pancreatic cancer patients is known as. Our experimental pancreatic cancer models revealed low levels of Merlin, which led to our ‘priming combination ‘ approach to FAK as less effective,” Dr. David Herrmann, the senior author of this study.
“We hope that by identifying which tumors cause less merlin which will allow us to identify those patients who are most likely to be the most benefitting from our combination approach.”
These findings will be part of a new clinical study in collaboration with Melbourne-based Amplia Therapeutics Limited. Phase II clinical trials for its FAK inhibitor AMP945 will begin next year, in Phase II clinical trials. The aim is to determine if the approach is efficient in patients.
“It is exciting for Amplia to be able to work with Garvan’s experience in FAK biology as well as cancer biology and clinical expertise. Dr John Lambert, Amplia CEO and Managing Director says that the preclinical results have provided valuable insight and have influenced our decision to move AMP945 the company’s FAK inhibitor, to clinical trials in Phase II for pancreatic cancer patients.
“The survival rates of pancreatic ductal carcinoma patients are extremely low and have been largely unchanged for many decades,” adds Professor Timpson. “Our method is an exciting and new clinically relevant avenue to improve current treatments, and could bring about a positive change for patients.”
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